Transcription factors are involved in a large number of human diseases such as cancers for which they account for about 20% of all oncogenes identified so far. For long time, with the exception of ligand-inducible nuclear receptors, transcription factors were considered as “undruggable” targets. Advances knowledge of these transcription factors, in terms of structure, function (expression, degradation, interaction with co-factors and other proteins) and the dynamics of their mode of binding to DNA has changed this postulate and paved the way for new therapies targeted against transcription factors. Here, we discuss various ways to target transcription factors in cancer models: by modulating their expression or degradation, by blocking protein/protein interactions, by targeting the transcription factor itself to prevent its DNA binding either through a binding pocket or at the DNA-interacting site, some of these inhibitors being currently used or evaluated for cancer treatment. Such different targeting of transcription factors by small molecules is facilitated by modern chemistry developing a wide variety of original molecules designed to specifically abort transcription factor and by an increased knowledge of their pathological implication through the use of new technologies in order to make it possible to improve therapeutic control of transcription factor oncogenic functions.

Ionizing radiation and radiomimetic anticancer agents induce clustered DNA damage, which are thought to reflect the biological severity. Escherichia coli Nth and Fpg and nuclear extracts from XRS5, a Chinese hamster ovary Ku-deficient cell line, have been used to study the influence on their substrate recognition by the presence of a neighboring damage or an abasic site on the opposite strand, as models of clustered DNA damage. These proteins were tested for their efficiency to induce a single-strand break on a 32 P-labeled oligonucleotide containing either an abasic (AP) site, dihydrothymine (DHT), 7,8-dihydro-8-oxo-2deoxygua-nine, or 7,8-dihydro-8-oxo-2deoxyadenine at positions 1, 3, or 5 base pairs 5 or 3 to either an AP site or DHT on the labeled strand. DHT excision is much more affected than cleavage of an AP site by the presence of other damage. The effect on DHT excision is greatest with a neighboring AP site, with the effect being asymmetric with Nth and Fpg. Therefore, this large inhibition of the excision of DHT by the presence of an opposite AP site may minimize the formation of double-strand breaks in the processing of DNA clustered damages.Radiation and radiation mimetic anticancer agents cause DNA damage, and it is thought that clustered damage (in which at least two damages are produced within less than 10 base pairs) is implicated in the biological severity of radiation since it is less repairable (1, 2). The complexity of radiationinduced clustered DNA damage increases on increasing the ionizing density of the radiation (LET).1 From track structure simulations, ϳ20% of double-strand breaks are associated with other damages for low LET radiation but increased to Ͼ20% for double-strand breaks induced by high LET ␣-radiation (3). Indirect experimental evidence supporting the role of DNA damage complexity comes from the reduced repairability of double-strand breaks induced in cellular DNA by high LET radiation (4, 5) and the increased complexity of single-strand breaks on increasing radiation quality as revealed using cell extracts (6 -9). If base damages within a cluster are on opposite strands and both excised, this gives rise to double-strand breaks. Therefore, it is of great significance to understand the way in which several damages in close proximity are recognized/processed by the cell.Although the chemical nature of oxidative damage produced by oxidative stress and by ionizing radiation are similar, the unique feature of ionizing radiation and radiation mimetic agents is their ability to produce clustered damage. There are only few studies about the excision of a damage substrate in the vicinity of another damage. In particular, synthesized oligonucleotides containing damage at specific sites were used to focus on the efficiencies of endonucleases VIII (Nei) and III (Nth) to excise either thymine glycol or DHT when opposite a singlestrand gap (10) as well as the efficiency of Fpg to excise 8-oxo-G or AP site opposite a gap (11) or 8-oxo-G near a formylamine on the same strand (12). Chaudhry...

A major DNA lesion is the strongly mutagenic 8-oxo-7,8-dihydroguanine (8-oxoG) base, formed by oxidative attack at guanine and which leads to a high level of G.C-->T.A transversions. Clustered DNA damages are formed in DNA following exposure to ionizing radiation or radiomimetic anticancer agents and are thought to be biologically severe. The presence of 8-oxoG within clustered DNA damage may present a challenge to the repair machinery of the cell, if the OGG1 DNA glycosylase/AP lyase protein, present in eukaryotic cells, does not efficiently excise its substrate, 8-oxoG. In this study, specific oligonucleotide constructs containing an 8-oxoG located in several positions opposite to another damage (5,6-dihydrothymine (DHT), uracil, 8-oxoG, AP site, or various types of single strand breaks) were used to determine the relative efficiency of purified human OGG1 and mammalian XRS5 nuclear extracts to excise 8-oxoG from clustered damages. A base damage (DHT, uracil, and 8-oxoG) on the opposite strand has little or no influence on the rate of excision of 8-oxoG whereas the presence of either an AP site or various types of single strand breaks has a strong inhibitory effect on the formation of a SSB due to the excision of 8-oxoG by both hOGG1 and the nuclear extract. The binding of hOGG1 to 8-oxoG is not significantly affected by the presence of a neighboring lesion.